While performing a DNA microarray gene expression analysis in collagen-induced arthritis (CIA), we discovered that a poorly-characterized gene, follistatin-like 1 (FSTL-1), was highly overexpressed in mouse paws during the early stages of arthritis. Especially-high expression was observed at the interface of synovial pannus and eroding bone, suggesting a role in joint destruction. Our Preliminary Studies provide strong evidence for a role for FSTL-1 in arthritis. Over-expression of FSTL-1 in mice resulted in severe paw swelling and arthritis, while neutralization of endogenous FSTL-1 ameliorated arthritis. We have also observed elevated expression of FSTL-1 in synovial tissues of patients with rheumatoid arthritis. Finally, we have now made the surprising observation that FSTL-1 induces maturation of IL-17-producing Th17 cells from naove CD4+ T cells. This finding represents a novel pathway for induction of Th17 cells, which have recently been shown to play a central role in autoimmunity, and whose maturation had previously been thought to require IL- 6 and TGF-. The current application will test the hypothesis that FSTL-1 plays a central role in arthritis and will explore the possibility that neutralization of FSTL-1 represents a novel therapeutic approach to the treatment of arthritis. The first Specific Aim is to determine the mechanism by which FSTL-1 induces inflammation. We will determine how FSTL-1 induces Th17 cells in vitro, whether FSTL-1 acts by a T cell receptor-dependent or independent pathway, whether FSTL-1 mediates its effect through a cell surface receptor, the FSTL-1 domain(s) responsible for the activity of FSTL-1 and whether FSTL-1 induces Th17 cells in vivo. The second Specific Aim is to determine the factors regulating FSTL-1 expression, including the tissue and cellular sources of FSTL-1 and the signals that induce FSTL-1 expression. The third Specific Aim is to determine the role of FSTL-1 in arthritis by overexpressing it, by neutralizing it in vivo with antibodies as well as by creating a conditional knockout. Understanding the properties of this novel protein will result in a better understanding of arthritis and possibly lead to new therapeutic targets. PUBLIC HEALTH RELEVANCE We have discovered a protein that plays a novel role in arthritis. Characterization of the properties of this protein is likely to lead to a better understanding of arthritis and possibly new therapies. [unreadable] [unreadable] [unreadable]